A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988), demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
Nucleotide sequencing of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313, 277 (1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease [Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)].
The compound N-(2(R)-hydroxy-1(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(2-b enzo[b]furanylmethyl)-2(S)-N'-(t-butylcarboxamido)-piperazinyl))-pentaneami de disclosed in U.S. Pat. No. 5,646,148, issued Jul. 8, 1997, and referred to herein as "Compound A," is a potent inhibitor of HIV protease and is useful in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of AIDS or ARC (AIDS related complex), without significant side effects or toxicity. ##STR1##
One substantial and persistent problem in the treatment of AIDS has been the ability of the HIV virus to develop resistance to the individual therapeutic agents employed to treat the disease. Thus, a need remains for an efficacious and long lasting therapy for AIDS which lowers HIV viral levels of patients to undetectable levels and raises CD4 cell counts for prolonged periods of time without the development of resistance. Therefore, it is an object of the invention to provide a combination therapy which lowers HIV viral levels below the limit of detection. It is another object of the invention to increase the count of CD4 cells for prolonged periods of time. Furthermore, it is an object of the invention to achieve both of these favorable results for extended periods of time without the development of resistance to the therapies.
Applicants have discovered that the combinations of this invention are effective inhibitors of HIV protease. In the present invention, Applicants co-administer a potent HIV protease inhibitor, Compound A, or pharmaceutically acceptable salts or esters thereof, with one or more nucleoside reverse transcriptase, non-nucleoside reverse transcriptase inhibitors, or protease inhibitors. Optionally, Compound A, or pharmaceutically acceptable salts or esters thereof, is co-administered with Zidovudine and Lamivudine. This combination therapy is a method to enhance the effectiveness in treating AIDS and to preclude the development of resistance to the individual therapeutic agents.